Elucidating the genetic risk of obesity through the human blood plasma proteome

Obesity is affecting an increasing number of individuals worldwide, but the complex interplay between genetic, environmental and lifestyle factors that control body weight is still poorly understood. Blood circulating protein are confounded readouts of the biological processes that occur in different tissues and organs of the human body. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1,000 blood circulating proteins and body mass index (BMI) in three studies, including over 4,600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We report 152 protein associations with BMI that replicate in at least one other study. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with three proteins (LEPR, IGFBP1, and WFIKKN2), a protein-to-BMI relationship for three proteins (AGER, DPT, and CTSA), and a BMI-to-protein relationship for 21 other proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets and further elucidate the biological role of these proteins in pathologies associated with obesity.